… at least according to my preset standard. I am now on Derek Lowe’s blogroll. Now that’s an honor! It also explains the considerable uptick in traffic around here.
We just got the referee and editor comments back on a paper we’ve been trying to get out for some time now. We first aimed high with a glamor mag and got some very encouraging reviews back from the editor but they were ultimately asking us to do far more than we can reasonably do (essentially asking us for experiments that would require us to develop a collaboration because we have no expertise in the type of very technically challenging and error-prone experiments they asked for) so we decided to shoot a tad lower and go for a very nice but non-glamour mag journal. We just got revision comments back from that review and I’m a tad confused by the comments from the editor.
We had the standard 2 referee report. 1 referee is clearly on our side, in fact, she said “now acceptable for publication” in the review and also noted that we had appeased the comments of both referees. I was pretty happy about that. The other reviewer didn’t seem so happy and has asked us to do yet more experiments including several that they did not ask for the first time around (this frustrates me to no end, if you didn’t think of it the first time then don’t ask for it the second time). If we did all the experiments suggested by the reviewer we would end up with about 15 multi panel figures. This is obviously excessive. I should qualify that all the experiments suggested are very interesting and we would like to do them but at some point you have to consider that a paper can only be so long and can only fry so many fish.
The interesting thing was the comment from the reviewing editor. They state right up front that the manuscript is potentially acceptable for publication and that they want to see a revised manuscript soon but they use the words “major revisions”. They also say that they are going to carefully review the manuscript and the response to the reviewers suggesting that they are not going to send it back to the referees (one clearly said accept anyway). The language is a bit cryptic so while I don’t think they are going to send it back to the referee that we have not fully convinced I cannot be 100% certain. The language of the editors really suggests to me that they would like to see the paper in the journal.
We would be very happy to have this manuscript published in this journal so we don’t want to blow the opportunity by taking anything for granted. If we do all that the non-convinced reviewer has asked us to do we have 4-6 months of work ahead of us before we can get a revision in. This thought makes me sick to my stomach because we have advanced this work significantly into another area and we are almost ready to get that paper submitted too but it has to wait on this one. On the other hand, we can do a completely different experiment, which the reviewer has not asked for, that would very strongly support our contention but through a negative rather than positive result. That experiment would take less than a week. I am strongly inclined to do the fast experiment and make considerable text revisions and get this puppy back in. It does seem that the editors are on our side and a quick turn-around would hopefully catch them while they are still feeling good about what we have done.
So, dear reader, what do you think? Am I off my rocker or does this sound like a reasonable path to acceptance?
to Montreal! Having lived in Montreal for 3 years as a postdoc at McGill I’m about as excited as I can be to be headed back to my old stomping grounds for the International Association for the Study of Pain meeting. Mrs. JP and I will be there for a week and are both attending the conference. This will be Mrs. JP’s first time at the conference and our first time going to a conference together (the basic and clinical mix at this conference has provided the opportunity). Should be exciting!
This is the first IASP meeting on the new two year rotation (next one is in Japan 2012 and then to Argentina 2014). The schedule for this meeting is very strong (IASP is always good) but the growth in the field is readily evident from this year’s line-up of talks and posters. I may try to blog the conference but more likely I’ll be sending out tweets.
Pharm 551A class, there will be no posts this week for class content since I won’t be around.
This is almost unbelievable. Apparently a federal judge has blocked the Obama administration’s change to stem cell research policy.
There’s this gem of a paragraph at Forbes on the story:
A federal appeals court had ruled that two fellow plaintiffs – doctors who do research with adult stem cells, James Sherley of the Boston Biomedical Research Institute and Theresa Deisher of AVM Biotechnology – were entitled to sue over the new guidelines, prompting U.S. District Judge Royce Lamberth on Monday to reverse a decision he made in October when he dismissed the lawsuit.
Sherley and Deisher allege that the guidelines will result in increased competition for limited federal funding and will injure their ability to compete successfully for National Institutes of Health stem cell research money.
I almost fell over when I read that so went searching for confirmation and found this at USA Today:
Lamberth’s reversal follows a federal appeals court ruling that allowed two adult-stem-cell researchers to pursue a lawsuit, claiming that the new guidelines would increase competition for limited federal funds and that it violated federal law.
Lamberth said that the “injury” of increased competition that James Sherley of the Boston Biomedical Research Institute and Theresa Deisher of AVM Biotechnology would face “is not speculative. It is actual and imminent. Indeed, the guidelines threaten the very livelihood of plaintiffs Sherley and Deisher.”
I really don’t know what to say but this seems like a dangerous precedent to me from Judge Lamberth. There is obviously more to the ruling than the dangers of competition for NIH funding (seriously, I can’t believe this) as part of the ruling is based on anti stem cell interests but this NIH thing appears to have played a part. And, yes, if you think you recognize the name James Sherley from something else, you probably do.
UPDATE: In case you don’t go all the way down in the comments, look what DM found
My lab dabbles in mTOR work so I pretty regularly scan pubmed for new papers with mTOR in the title or abstract. Its a fast moving field so there’s lots to keep up with and usually 20-30 new papers out for each of my saturday morning mTOR searches. This morning I stumbled upon this little gem:
Burd et al., PLoS One Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men.
Now, I’m no exercise physiologist so I’m not going to go into details on the background of the work but I do know enough to know that stimulating protein synthesis in muscles through weight training is your goal. This builds muscle mass, makes you stronger/faster — all those reasons that we go to the gym in the first place. The question is how best to do that. mTOR, for those that don’t know, is a kinase involved in regulating protein synthesis. Its a complicated cascade but the basics are that stimulating mTOR in a cell type leads to more protein synthesis. If a specific type of exercise stimulates mTOR activity, this is probably a good thing to achieving results from your workout. In the paper they had young men do three types of exercise (on a leg extension machine): 1) low rep / high weight, 2) medium rep / medium weight and 3) low weight / high rep. In a nutshell, they found that low weight / high rep was the best way to go to stimulate mTOR in muscle fibers. So what does this mean?
Can this get any worse? On Monday this story on financials and drugs coming off patent vs. the pipeline for Lilly is in the NYTimes. Then, yesterday, this story comes out about Lilly’s failed gamma-secretase trial for Alzheimer’s. Derek Lowe has a nice run-down on this latest failure plus links to his previous musings about this up today. Doesn’t sound good for Lilly. And what does this mean for all the hype on the Alzheimer’s biomarkers last week? Looks like major turmoil ahead to me.
Go read. I have nothing else to say other than: Bravo!!
I have a few minutes so I would like to highlight this paragraph written by editor in chief Dr. John Maunsell:
Another troubling problem associated with supplemental material is that it encourages excessive demands from reviewers. Increasingly, reviewers insist that authors add further analyses or experiments “in the supplemental material.” These additions are invariably subordinate or tangential, but they represent real work for authors and they delay publication. Such requests can be an unjustified burden on authors. In principle, editors can overrule these requests, but this represents additional work for the editors, who may fail to adequately referee this aspect of the review.
In my opinion this is absolutely correct and gets right to the heart of what I think is wrong with science today. Our papers are ultimately about ideas and the experiments that either support or reject those ideas. The constant you just need one more piece of supporting evidence for everything mindset of many reviewers (I include myself in falling into this trap) is not useful to the process. The ideas in a given paper may or may not stand the test of time and that one more piece of supporting evidence is unlikely to have any influence on what that test of time will determine. The point is to get potentially influential ideas out there and to get them out earlier rather than later. Post publication experimental scrutiny is and will always be how the test of time determines the validity of new scientific concepts.
Genomic Repairman has a little rant up over at Labspaces in which he becomes exasperated at someone in his field who has had two R01 continuously for at least 26 years. Abel Pharmboy has already dealt with this in hilarious fashion (weedhopper? — haven’t heard that one before) so I won’t belabor the obvious; however, I would like to point out a few long-standing grants in my area — pain research — that have had a profound impact on our understanding of pain.
Let’s start with what, to my knowledge, is the granddaddy of them all in the pain field: Ed Perl’s 36 year old (expired in 2008) R01 entitled “SPINAL AND PROJECTION MECHANISMS RELATED TO PAIN”. If you’ve got a neuroscience or general medicine textbook handy, look up the word “nociceptor”. These are pain sensing neurons in the peripheral nervous system. Now go read what the textbook says. There should be something there about how these neurons are noxious stimulus detectors that specifically respond to stimulation in the noxious range. They also respond to many chemicals and temperature changes into the too hot and cold to handle range. What you just read is work that was funded by this R01. Similarly, if you are interested in how noxious input is processed in the dorsal horn of the spinal cord much of what you will find in the textbooks came from Ed Perl’s work funded by this R01.
How about another old one (the grant, not the person): Gerald (Jerry) Gebhart’s 28 year old R01 entitled “MECHANISMS AND MODULATION OF VISCERAL PAIN”. Of his 300+ publications, many of them were funded by this long-standing R01. Like Ed Perl’s grant, to understand the contribution that this continuously funded grant has had on our appreciation of pain processing is quite simple — pick up a textbook. Much of what we know about visceral pain has come from work done in this grant. The work spans from understanding how descending modulation systems (periaqueductal grey (PAG) and rostral ventromedial medulla (RVM)) amplify pain of a visceral origin to the receptors and molecules responsible for causing visceral pain. Pretty important stuff and, I might add, if you are working in Pharma trying to develop drugs to target visceral pain, chances are you are relying pretty heavily on Jerry’s work not only for target identification but also for the techniques that you will use to validate whether your drugs are doing what you want them to do. You may have also noted from that link above that Dr. Gebhart is also the current President of the International Association for Pain.
Let’s do one more shall we… Allan Basbaum’s 33 year old R37 (Merit Award) entitled “BRAINSTEM CONTROL OF PAIN TRANSMISSION”. Where to start with this one? Anatomical mechanism of analgesic action of opioids: check. Anatomy of bulbospinal projections to the dorsal horn of the spinal cord: check. The list could go on and on. Again, this is all standard textbook stuff now. One thing that really interests me about this grant is the remarkable transformation that the work has undergone as state-of-the-art techniques in biomedical science have changed. Perhaps more than any one else I can think of in the field, Dr. Basbaum’s lab has not only kept up but consistently led in continuing to push the edge in terms of using the latest and greatest techniques to address problems in new and exciting ways. He’s also the current Editor in Chief for Pain, the most influential journal in the field.
There are many more such examples in the field but I think you get the point. If you search for all 3 of the researchers I have highlighted above in NIH Reporter (all years, not active projects) you will note that these long-standing grants represent the bulk of the funding that each of these PIs have held over their careers. In my view this adds considerable stability to the field with very little sign of stagnation. Its interesting to check the abstracts for these grants in renewal years (generally every 5 years). You will note a remarkable change in the hypotheses being addressed and a real progression in the work from funding period to funding period. One might even argue (I would) that the titles don’t really fit the grant anymore but that’s part of the beauty of choosing a very general sounding title. I wish I would have done that for my first R01.
I totally missed that DrdrA hit this up too…
I’m gonna get to a full post on the process soon but have no time for that now. I just want to briefly describe the steps from the perspective of a primarily in vivo pharmacologist:
1. find your target
2. get some idea of structure activity relationship (SAR) for your target
3. design a high-throughput screen (HTS) — preferable two of them (functional and binding)
4. start making and screening compounds
lots of time and frustration passes (maybe frustration is not the right word but its hurry up and wait to get to where you want to be)
5. validate hits from screening
6. validate hits some more, go back to SAR
7. scale up hits for in vivo test
8. do in vivo test (start screaming and yelling if it works)
Number 8 would have been me (and very important turbo grad student) today.
I am a happy man… (and that new Arcade Fire album is pretty good too)
More on all of this later.
First off, WOW!!, this has easily been the busiest day ever on juniorprof. Many, many, thanks to Abelpharmboy, Zuska, Melissa McEwan and Almost Diamonds for linking here and sharing your support for the campaign and also to DM for all the support over on twitter for the #painresearchmatters campaign. I am humbled by all of your support and encouragement. Keep the tweets pouring in on twitter with the hashtag #painresearchmatters!
Now, onto our regularly scheduled program: Drug discovery in academia. To some of you this may seem like a strange thing to post about since the common perception is that there is no drug discovery (at least no REAL drug discovery) in academia. I have to admit, I tend to agree that drug discovery in academia is limited and oftentimes lacks the type of rigor that is really needed to develop a drug. For an extensive series of posts on industry vs. academic drug discovery head on over to Derek Lowe’s place. He has all his posts on the topic nicely categorized and they are a very interesting read. One of my all time favorites is this one where he points out that while the compound may be useful as an in vitro tool, it is likely less than useful as a scaffold for further drug development for very obvious reasons. This brings us to the bane of drug discovery: absorption, distribution, metabolism and excretion (ADME). This is something that industry does very well. After all, if you want to make a drug that enters the brain it damn sure better cross the blood brain barrier. ADME in academia, well, let’s just say, not so much. The reasons for this are likely pretty simple: its an important area of drug development but not the most exciting, by any stretch of the imagination (sorry you ADME specialists), and it often requires all sorts of rather expensive testing in model organisms that aren’t used often in academic labs. Its also highly compound-specific and this makes grant writing very hard (or so I hear).
On the other hand, there are very good reasons to do more drug discovery in academia. First, most of the disease models employed for drug development are created in academic labs. Ditto on the development of drug targets for diseases. Its also true that many, if not most, of the endogenous activators of receptors and enzymes have been discovered through the efforts of NIH-funded research. These endogenous ligands are usually the platforms on which additional drug scaffolds are made and academic pharmacologists are pretty darn good at generating structure activity relationships (SAR) for drug-receptor interactions. So what’s the hold-up? In my view its the nature of the academic beast. The medicinal chemists and in vivo and in vitro pharmacologists that are needed to bring a drug discovery effort to fruition just don’t have the opportunities to come together in an academic setting like they do in pharma industry. Pharma industry is built for this sort of thing. NIH grants are not. All of this adds up to major impediments to drug discovery in academia while the potential benefit is huge. Drugs developed through academic efforts have the potential to be much cheaper, target diseases were there is little, if any, potential profit margin (orphan drug programs aside) and would be a huge boon for NIH. Imagine how much easier justifying big increases in NIH funding would be if NIH funded labs were doing work that was leading directly (in the most literal sense of the word) to new therapies. I think this would be huge. Continue reading